In 1966 Cowles played the title role in Edward Albee's short-lived adaptation of James Purdy's comic novel Malcolm on Broadway at the Shubert Theatre.
Cowles' first film was the comedy drama Me, Natalie (1969) in which he played Harvey Belman. Al Pacino also made his debut in this film.
In 1980, he married Actress Kathleen Dezina, his All My Children co-star.
In 1983, Cowles joined The Mirror Theater Ltd's Mirror Repertory Company for their first repertory season, performing in Paradise Lost, Rain, Inheritors, and The Hasty Heart.
In 2010, Cowles played a supporting role in Martin Scorsese's film Shutter Island.
In 1983 he married Actress Christine Baranski with whom he had two daughters, Isabel (born 1984) and Lily (born 1987). In a New York Times profile of his wife, he was described as “the black sheep member of a family with ties" to Drexel banking and the Cowles Publishing Company. He was an enthusiastic motorcycle rider. Matthew Cowles died from congestive heart failure on May 22, 2014.
